GI- Histamine/ PUD Flashcards
What is histamine?
where is it stored?
when is it released?
- a naturally occurring endogenous amine that is synthesized in tissues by decarboxylation of histadine
- Stored in vesicles in mast cells in the skin, lung, and gastric mucosa
- stored in vesicles in circulating basophils
- released in response to antigen-antibody reaction or in response to certain drugs
What does histamine do?
- Histamine is an inflammatory mediator
- regulated gastric acid secretion
- regulates neurotransmission
- does not easily cross the BBB thus CNS effects are not evident
- effects mediated by H1, H2, & H3 receptors
How do histamine antagonists work?
- They do not prevent the release of histamine, but instead block the receptor where the histamine binds, blocking the response to histamine
- agents are classified by which receptor the antagonism occurs at
What does the H1 receptor do?
Where is the H1 receptro found?
- Smooth muscle contraction in lung and GI, vascular endothelium; release of NO, sensory nerve stimulation
- lungs- bronchoconstriction
- vascular smooth muscle- dilation–>hypotension and erythema ***predominant effect of histamine
- vascular endothelium- increased capillary permeability–>edema
- peripheral nerves- sensitization- itching, pain, sneezing
- heart- found in AV node; slows HR by slowing conduction
Where is the H2 receptor found?
What is its effect?
- Found in gastric parietal cells, cardiac muscle, and mast cells
-
heart- positive inotropic and chronotropic effects–>increase in HR and contractility
- coronary vasculature dilation (offsets constriction of H1)
- relaxes bronchial smooth muscle
-
stomach- Activation cAMP–> activates proton pump of parietal cells to secrete hydrogen ions
- increased gastric acid can lead to PUD, GERD
Where is the H3 receptor found?
What does it do?
- Located on the heart and presynaptic postganglionic SNS fibers
- stimulation causes inhibition of synthesis and release of histamine
- Some H2 antagonists may affect H3 receptors, which would ultimately cause an increase in histamine release
- Avoid rapid administration of agents known to cause histamine release (ex. atracurium) if pt has been pretreated with an H2 antagonist
- will have greater atracurium induced BP decrease in a pt pretreated with an H2 blocker than a pt pretreated with an H1 blocker
What kind of receptors are histamine receptors?
How do H1 and H2 antagonists interact with them?
- Seven-transmembrane GCPR
- H1 and H2 antagonists competetively and reversibly inhibit receptros on effector cell membranes
What do H1 antagonists treat?
H2 antagonists?
- H1 antagonists- allergic rhinitis
- H2 antagonists- inhibit acid gastric fluid secretion
How are H1 antagonists classified?
uses?
- Classified as first and second generation
- first generation- will also bind to muscarinic, serotonin, and alpha receptors, causing sedation
- second generation- more specific to H1 receptors; non-drowsy, decreases CNS toxicity
- Uses:
- rhinitis
- conjunctivitis
- urticaria
- pruritis
First generation H1 antagonist pharmacokinetics?
examples
- Pharmacokinetics:
- lipophilic
- neutral at physiologic pH
- examples
- diphenhydramine
- hydroxyzine
- promethazine
- chlorpheniramine
- Doxepin
Second generation H1 antagonist pharmacokinetics?
examples?
- pharmacokinetics
- Ionized at physiologic pH
- “albumin binding”- not sure what she meant by this, didnt see anything in book
- Examples
- Loratidine
- desloratidine
- acrivastine
- fexofenadine
H1 antagonists:
Are they well absorbed?
Concentrtation max?
PB?
metabolization?
E1/2t?
- Excellent absorption
- Plasma concentration max in about 2-3 hours
- protein binding 78-99%
- heptaically metabolized by CYP450
- E1/2t is variable
- chlorpheniramine >24 hours
- Acrivastine - 2 hours
What are some adverse effects of H1 antagonists?
- CNS toxicity- sedative effects
- Cardiac toxicity- QT interval prolongation
- Anticholinergic effects- pupillary dilation, dry eyes, dry mouth, urinary hesitancy
Why are H2 antagonists given?
What agents are available?
most potent vs least potent?
- Competitive antagonism of H2 receptors used to suppress gastric acid secretion by parietal cells
- Agents:
- The ones we use: Cimetidine, Ranitidine
- must give ahead of time: famotadine
- Nizatidine
- Potency:
- least: Cimetidine
- most: Famotadine
What are the clinical uses of H2 antagonists?
Doses
- treatment of duodenal ulce disease & GERD
- No effect on pH of fluid already in stomach
- unpredictable effect on volume of fluid present in stomach
- Chemophophylaxis prior to induction of GA
- Cimetidine 300 mg PO or IV 1-2 hours pre-op
- Famotadine 20-40 mg PO/ 20 mg IV am of surgery
- Ranitidine- 150 mg PO or 50 mg IV
What are the pharmacokinetics of the H2 antagonists?
absorption?
Concentration max?
PB?
Which ones cross the BBB?
- Rapid oral absorption, but first pass hepatic metabolism reduces bioavailability to 50%
- Plasma concentration max 1-3 hrs for PO admin
- PB 13-35%
- All cross BBB
- Cimetidine
- Ranitidine
- Famotidine
- Nizatidine
Which H2 antagonists are excreted renally?
Which are cleared principally by hepatic metabolism?
- Renal
- Nizatidine
- Hepatic
- Cimetidine
- ranitidine
- famotidine
What are the H2 antagonist side effects?
- Cimetidine will delay awakening from GA in pts with RF
- may have transient elevation of LFTs
- Rapid administration of Cimetidine and Ranitidine may cause bradycardia and hypotension
- give over 15-30 min
- Famotidine may be given over 2 minutes
- Decreased metabolism of drugs that undergo extensive hepatic extraction- propranolol, Diazepam
- by altering pH, may change rates of absorption of other drugs
Cimetidine may slow metabolism of what drugs?
(chart from book)
What are the three most important factors that cause PUD?
What are the goals of therapy?
- Causative factors:
- H.Pylori infection
- NSAID use
- smoking
- Goals of therapy?
- Reduce gastric acidity
- enhance mucosal defenses
- eliminate H. pylori
What drugs are used to treat PUD?
- To inhibit acid secretion:
- H2 antagonists
- PPIs
- anticholinergic agents
- To Neutralize gastric acid
- Antacids
- To protect gastric mucosa
- Sucralfate
- Colloidal bismouth
- Prostaglandins
- to Eradicate H.Pylori
- Antibiotics
How do PPIs work and what are the agents available?
- Block K-H-ATPase pump, inhibiting release of acid
- Agents:
- Lansoprazole
- pantoprazole
- esomeprazole
- omeprazole
- rabeprazole
PPI pharmacokinetics
absorption
MOA
metabolization
- Rapid absorption
- prodrug converted into active drug in parietal cell canaliculus
- forms a covalent bond with Proton pump
- short half life
- Hepatically metabolized by CYP2C19, 3A4
- crosses placenta
What are some adverse effects of PPIs?
- HA
- GI disturbance/nausea
- enteric infections
- long-term problems unknown (carcinoid tumors?)
What is Dicyclomine?
Adverse effects?
- An anticholinergic (muscarinic ACh receptor antagonist)
- used to decrease acid secretion
- less effective than H2 antagonist and PPIs
- Adverse effects:
- dry mouth, constipation, blurred vision, cardiac arrhythmia, urinary retention
What is Sucralfate?
What does it do?
- Complex salt of sucrose sulfate and aluminum hydroxide
- forms a viscous gel that binds to positively charged proteins (albumin, fibrinogen) and sticks to areas of ulceration
- protects ulcerative tissue from aggressive factors such as Pepsin, acid, bile salts
- Does NOT alter gastric pH
- provides symptomatic relief only
What are the adverse effects of Sucralfate?
What are other problems with it?
- Adverse effects:
- constipation
- little systemic absorption
- Other problems
- large tablets and frequent administration make it difficult for patients to use
- drug interactions by binding to drugs
What is Colloidal Bismouth?
What does it do?
- It is a coating agent used in PUD
- protects mucosa from acid and pepsin degradation
- forms a barrier
- stimulates mucosal bicarb and PGE2
- inhibits growth of H.Pylori
What is Misoprostol?
What is it used for?
What are adverse effects?
Contraindications?
- Prostaglandin analogue
- Used to prevent NSAID-induced ulcers
- Adverse effects:
- abdominal discomfort, diarrhea
- contraindications:
- pregnancy
What are the two treatment regimes for H.Pylori?
- Triple therapy:
- Amoxicillin
- clarithromycin
- PPI
- Quadruple therapy
- Tetracycline
- Metronidazole
- PPI
- Bismouth
